Osimertinib promising for EGFR-mutant NSCLC with leptomeningeal metastases
medwireNews: Patients with EGFR-mutant (m) non-small-cell lung cancer (NSCLC) and leptomeningeal metastases (LM) respond favorably to high daily doses of osimertinib, phase 1 BLOOM study data suggest.
Myung-Ju Ahn (Sungkyunkwan University School of Medicine, Seoul, Republic of Korea) and study co-authors say that “osimertinib has the potential to become a treatment option for patients with EGFRm NSCLC and LM previously treated with EGFR-TKI [tyrosine kinase inhibitor].”
Between April 2015 and October 2017, 41 patients whose disease had previously progressed on EGFR–TKI therapy were enrolled in the BLOOM trial. All patients received osimertinib 160 mg orally once a day for a median of 8.1 months, during which radiologic assessments were performed every 6 weeks, starting at baseline. There were 29 patients who had co-existing brain metastases, and consequently 20 of these patients had previously received brain radiotherapy.
Investigator assessment found that one patient achieved LM complete response, while neuroradiologic blinded independent central review (BICR) available for 37 patients identified 12 as achieving an LM complete response. An LM partial response was seen in 10 and 11 patients as determined by investigator and BICR, respectively, and the corresponding objective response rates (ORRs) were 27% and 62%.
LM responses lasted for a median of 15.2 months as evaluated by BICR and 18.9 months by investigator assessment.
Writing in the Journal of Clinical Oncology, Ahn et al speculate that discrepancies between investigator assessment and BICR are likely caused by the varying levels of expertise of the individuals involved and their use of different radiologic criteria.
The investigator-assessed central nervous system (CNS) ORR was 58% and the overall ORR (including CNS and non-CNS responses) was 41%.
Progression-free and overall survival as evaluated by investigator assessment were deemed “promising” by Ahn et al, at a median of 8.6 and 11.0 months, respectively. At 12 months, 42% of patients remained progression-free and 48% were alive. The most common site of first progression was non-CNS followed by CNS and LM, according to both BICR and investigator assessments.
Prior brain radiotherapy did not influence ORR, as comparable rates of 55% and 57% were observed among those who did and did not receive prior brain radiotherapy.
Subgroup analysis showed that patients with an EGFR T790 mutation had lower response rates, and a shorter duration of response than T790M-negative patients. The investigators suggest that the clinical benefit of osimertinib in T790M-negative patients may be influenced by the fact that these patients were required to have stable non-CNS disease and were more likely to have received prior-whole brain radiation therapy.
Grade 3 or above adverse events (AEs) occurred in 27 patients, nine of whom discontinued their treatment as a result. Of note, osimertinib was possibly causally related to one grade 4 case of pneumonitis. Despite this, the researchers highlight that “no new safety concerns were identified.”
The study authors note the “encouraging” observation that neurologic function improved in 57% of the patients with abnormal assessment at baseline, emphasizing that “most neurologic deficits caused by LMs are considered irreversible.”
Overall, they say that “osimertinib demonstrated a clinically meaningful benefit across all efficacy end points tested,” but they conclude: “Additional studies are required to confirm these findings using the 80-mg dose.”
By Hannah Kitt
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